Since the 1930s it has been known that a severe reduction in energy intake (caloric restriction, CR) delays the onset of most age-related diseases and extends both mean and maximum lifespan in mammals. Drugs or therapies that mimic these effects would be of enormous benefit to society but their development requires a better understanding of how CR works. It has been proposed that the Sir2/SIRT1 deacetylase is a critical mediator of CR's effects and indeed, Sir2 is necessary for lifespan extension by CR in simple organisms such as yeast and flies. Small molecules that activate Sir2, such as resveratrol, extend the lifespan of diverse species and are considered potential CR mimetics. Resveratrol has already been shown to prevent a wide variety of disease processes and can reduce all-cause mortality in mammals, making it arguably the most promising candidate for a CR mimetic. At present, however, both the involvement of SIRT1, the closest mammalian Sir2 homolog in CR, and the mechanism of resveratrol's effects remain topics of heated debate. Resolving these issues is one of the most important endeavors in the aging field today because these findings may lead to new insights into the nature of functional decline and diseases that occur as part of the aging process as well as opportunities for therapeutic interventions. The broad goal of this proposal is to determine the involvement of SIRT1 in the beneficial effects of both CR and resveratrol in mammals using tissue-specific and inducible SIRT1 knockout mice. In each case both cancer-preventive and metabolic effects will be tested in the absence of SIRT1. The specific aims are 1) to determine whether protection from tumorigenesis by CR and/or resveratrol is mediated by SIRT1 in the /\pc"'"'* model, 2) to test whether protection from fatty liver and insulin resistance by resveratrol are mediated via SIRT1, and 3) to test whether metabolic adaptations to fasting and CR require SIRT1 in vivo. CR has been shown to be protective against most of the major causes of death and disability in the Western world, including cancer, cardiovascular disease, and the metabolic syndrome. The experiments outlined in this proposal will resolve an important controversy, help to reveal how CR works at the molecular level, and may point the way to the development of effective human therapeutics in a number of disease areas.